Low dose topiramate/phentermine composition and methods of use thereof

ABSTRACT

A method for effecting weight loss by administering a combination of topiramate and phentermine is provided. The phentermine is generally administered in immediate release form, in a daily dose in the range of 2 mg to 8 mg, in combination with a daily dose of topiramate selected to prevent the loss of effectiveness of phentermine alone. Methods for treating obesity, conditions associated with obesity, and other indications are also provided, as are compositions and dosage forms containing low doses of phentermine and topiramate, e.g., 3.75 mg phentermine and 23 mg topiramate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 14/048,576, filedOct. 8, 2013, which is a continuation of U.S. Ser. No. 12/481,540, filedJun. 9, 2009, now U.S. Pat. No. 8,580,298, which is acontinuation-in-part of U.S. Ser. No. 12/135,953, filed Jun. 9, 2008.The contents of each of these applications are incorporated by referencein their entirety.

BACKGROUND OF THE INVENTION

The prevalence of obesity in both children and adults is on the rise infirst world countries, especially in the United States, as well as inmany developing countries such as China and India. Many aspects of aperson's life are affected by obesity, from physical problems such asknee and ankle joint deterioration, to emotional problems resulting fromself-esteem issues and society's attitude towards heavy people. Themedical problems caused by obesity can be serious and oftenlife-threatening and include diabetes, shortness of breath and otherrespiratory problems such as asthma and pulmonary hypertension,gallbladder disease, dyslipidemia (for example, high cholesterol or highlevels of triglycerides) and dyslipidemic hypertension, osteoarthritisand other orthopedic problems, reflux esophagitis (heartburn), snoring,sleep apnea, menstrual irregularities, infertility, problems associatedwith pregnancy, gout, cardiovascular problems such as coronary arterydisease and other heart trouble, muscular dystrophy, and metabolicdisorders such as hypoalphalipoproteinemia, familial combinedhyperlipidemia, and Syndrome X, including insulin-resistant Syndrome X.In addition, obesity has been associated with an increased incidence ofcertain cancers, notably cancers of the colon, rectum, prostate, breast,uterus, and cervix.

Obesity substantially increases the risk of morbidity from hypertension,dyslipidemia, type II diabetes, coronary heart disease, stroke,gallbladder disease, osteoarthritis and endometrial, breast, prostate,and colon cancers. Higher body weights are also associated withincreases in all-cause mortality. Many of these problems are relieved orimproved when the afflicted individual undergoes permanent significantweight loss. Weight loss in these individuals can also promote asignificant increase in longevity.

Strategies for treating obesity and related disorders have includeddietary restriction, increased physical activity, pharmacologicalapproaches, and even surgery, with the choice depending, at least inpart, on the degree of weight loss one is attempting to achieve as wellas on the severity of obesity exhibited by the subject. For example,treatments such as a low-calorie, low-fat diet and/or regular exerciseare often adequate with individuals who are only mildly overweight. Thedifficulty in maintaining long-term weight loss through diet andbehavior modification, however, has led to an increasing interest inother avenues for treatment, particularly pharmacotherapy.

Traditional pharmacological interventions typically induce a weight lossof between five and fifteen kilograms; if the medication isdiscontinued, renewed weight gain often ensues. Surgical treatments arecomparatively successful and are reserved for patients with extremeobesity and/or with serious medical complications.

The above treatments can be enhanced by controlled use ofover-the-counter appetite suppressants including caffeine, ephedrine andphenylpropanolamine (Acutrim®, Dexatrim®). Moreover, prescriptionmedications including amphetamine, diethylpropion (Tenuate®), mazindol(Mazanor®, Sanorex®), phentermine (Fastin®, Ionamin®), phenmetrazine(Preludin®), phendimetrazine (Bontrol®, Plegine®, Adipost®, Dital®,Dyrexan®, Melfiat®, Prelu-2®, Rexigen Forte®), benzphetamine (Didrex®)and fluoxetine (Prozac®) are often used in the treatment of seriouslyoverweight and/or obese subjects or patients.

While society has seen tremendous advances in the field ofpharmaceuticals, there are, of course, drawbacks to the administrationof any given pharmaceutical agent. Sometimes, the disadvantages, or“side effects,” are so severe as to preclude administration of aparticular agent at a therapeutically effective dose. Furthermore, manyagents in the same therapeutic class display similar side effectprofiles, meaning that patients either have to forego therapy or sufferfrom varying degrees of side effects associated with the medication ofchoice.

In U.S. Pat. No. 7,056,890 to Najarian and U.S. Patent Publication Nos.US 2006/0234950 A1, US 2006/0234951 A1, and US 2006/0234952 A1 toNajarian, all of common assignment herewith to Vivus, Inc. (MountainView, Calif.), a combination therapy for treating obesity and effectingweight loss is provided wherein a synergistic effect between the activeagents enables dose reduction and a concomitant alleviation of sideeffects typically associated with each active agent. One of the activeagents is an anti-convulsant agent, e.g., topiramate, and the secondactive agent is a sympathomimetic agent, typically a sympathomimeticamine such as phentermine. In U.S. patent application Ser. No.12/135,935, also of common assignment herewith, an escalating dosingregimen is described for administering topiramate alone or incombination with a second therapeutic agent such as phentermine, whereinthe second agent is selected so as to directly or indirectly reduce theside effects associated with one or both of the agents administered. By“indirectly” reducing side effects is meant that a first pharmaceuticalagent allows the second agent to be administered at a lower dose withoutcompromising therapeutic efficacy, thus reducing dose-dependent unwantedeffects.

Topiramate (2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranosesulfamate) is a broad-spectrum neurotherapeutic agent approved by theFDA and the regulatory agencies of many other countries for thetreatment of certain seizure disorders and the prevention of migraineheadaches. E. Faught et al. (1996) Neurology 46:1684-90; Karim et al.(1995) Epilepsia 36 (S4):33; S. K. Sachdeo et al. (1995) Epilepsia36(S4):33; T. A. Glauser (1999) Epilepsia 40 (S5):S71-80; R. C. Sachdeo(1998) Clin. Pharmacokinet. 34:335-346). There has also been evidencethat topiramate is effective in the treatment of diabetes (U.S. Pat.Nos. 7,109,174 and 6,362,220), neurological disorders (U.S. Pat. No.6,908,902), depression (U.S. Pat. No. 6,627,653), psychosis (U.S. Pat.No. 6,620,819), headaches (U.S. Pat. No. 6,319,903) and hypertension(U.S. Pat. No. 6,201,010). However there have been adverse effectsassociated with the use of topiramate in humans, such as cognitivedulling and word finding difficulties, which can discourage many obesepatients from taking this drug.

Phentermine was approved by the FDA as an appetite suppressant in 1959,and phentermine hydrochloride has been used as a weight loss agent sincethe 1970s, e.g., under the brand names Adipex-P®, Fastin®, Zantril®, andothers. Although the FDA warned against combining phentermine with asecond active agent following the reports of cardiac and pulmonaryproblems associated with the “Fen-Phen” product (in which phenterminewas combined with fenfluramine, and later with a related drug,dexfenfluramine), it has since been found that a safe and effectiveweight loss treatment is provided by combining phentermine with anactive agent that mitigates phentermine's side effects and enablesadministration of a much lower dose of phentermine than in “Fen-Phen”(containing 30 mg or 37.5 mg phentermine hydrochloride). See U.S. Pat.No. 7,056,890 to Najarian and U.S. Patent Publication Nos. US2006/0234950 A1, US 2006/0234951 A1, and US 2006/0234952 A1 to Najarian,cited above.

It has now been discovered that a significantly lower dose combinationproduct is effective in achieving weight loss, treating obesity, andtreating conditions associated with obesity and excessive weight. Thepresent invention is directed to this product and methods of using theproduct. The invention provides a number of important advantagesvis-à-vis prior weight loss therapies, as will be described in detailherein.

SUMMARY OF THE INVENTION

Accordingly, in a first embodiment, the present invention is directed toa method for effecting weight loss in a subject by administeringcontinually over a significant period of time a daily dose ofphentermine in the range of 2 mg to 8 mg and in combination therewith adaily amount of topiramate selected to prevent the loss of effectivenessof phentermine alone. Generally, the combination of these active agentsis administered orally. The agents may be administered at differenttimes of day, with the phentermine administered earlier in the day andthe topiramate administered later in the day, in the afternoon orevening. Normally, however, the two agents are administeredsimultaneously using one or more dosage forms that provide for immediaterelease of the phentermine and controlled release of the topiramate. Inan exemplary embodiment, the phentermine and topiramate are administeredin a single dosage form that provides for immediate release of thephentermine and both delayed and sustained release of the topiramate.

In another embodiment, the invention is directed to a method foreffecting weight loss in a subject by administering continually over asignificant period of time a daily dose of 3.75 mg phentermine and, incombination therewith, a daily dose of 23 mg topiramate.

In another embodiment, the invention is directed to a method foreffecting weight loss in a subject by administering continually over asignificant period of time a daily dose of 7.5 mg phentermine and, incombination therewith, a daily dose of 46 mg topiramate.

In these methods, the daily doses of topiramate and phentermine may alsobe administered to treat one or more conditions associated with excessweight or obesity. These conditions include, without limitation,diabetes, respiratory disorders, gallbladder disease, dyslipidemia,orthopedic problems, reflux esophagitis, snoring, sleep apnea, menstrualirregularities, infertility, pregnancy complications, gout,cardiovascular problems, muscular dystrophy, metabolic disorders, andcertain cancers. Accordingly, in a further embodiment, the inventionrelates to a method as enumerated above which further involvessimultaneously treating the subject for a condition associated withexcess weight or obesity.

In another embodiment, a composition is provided for administration to asubject in order to effect weight loss, wherein the composition contains2 mg to 5 mg phentermine and 17 mg to 23 mg topiramate. An exemplarysuch composition contains 3.75 mg phentermine and 23 mg topiramate.Generally, the composition is an orally administrable unit dosage formthat contains both active agents. Certain dosage forms of the inventionprovide for immediate release of the phentermine and controlled releaseof the topiramate.

In a further embodiment, a packaged pharmaceutical preparation isprovided that contains a composition of the invention in a sealedcontainer, with instructions for administration, typicallyself-administration, of the composition. Generally, the packagedpreparation contains a plurality of orally administrable unit dosageforms, with, preferably, each individual dosage form in a separatesealed housing, e.g., as in a blister pack.

In still another embodiment, the method, composition, and packagedpreparation of the invention are adapted to administer phentermine andtopiramate to treat epilepsy.

In still another embodiment, the method, composition, and packagedpreparation of the invention are adapted to administer phentermine andtopiramate to treat an impulse control disorder.

In still another embodiment, the method, composition, and packagedpreparation of the invention are adapted to administer phentermine andtopiramate to treat a psychiatric disorder such as depression, panicsyndrome, generally anxiety disorder, phobic syndromes, mania, manicdepressive illness, hypomania, unipolar depression, stress disordersincluding post-traumatic stress disorder (“PTSD”), somatoform disorders,personality disorders, psychosis, and schizophrenia.

In still another embodiment, the method, composition, and packagedpreparation of the invention are adapted to administer phentermine andtopiramate to treat adolescent and juvenile obesity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a summary of the plasma concentration of controlledrelease topiramate according to the present invention versus topiramate(Topamax®) in normal obese subjects.

FIG. 2 depicts the mean plasma phentermine concentrations versus timefor subjects administered phentermine in combination with controlledrelease topiramate and phentermine in combination with immediate releasetopiramate (Topamax®).

DETAILED DESCRIPTION OF THE INVENTION Definitions and Nomenclature

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example, “anactive agent” refers not only to a single active agent but also to acombination of two or more different active agents, “a dosage form”refers to a combination of dosage forms as well as to a single dosageform, and the like.

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by one of ordinary skill in the artto which the invention pertains. Specific terminology of particularimportance to the description of the present invention is defined below.

When referring to an active agent, applicants intend the term “activeagent” to encompass not only the specified molecular entity but also itspharmaceutically acceptable, pharmacologically active analogs,including, but not limited to, salts, esters, amides, prodrugs,conjugates, active metabolites, and other such derivatives, analogs, andrelated compounds as will be discussed infra. Therefore, reference to“phentermine” encompasses not only phentermine per se but also salts andother derivatives of phentermine, e.g., phentermine hydrochloride. It isto be understood that when amounts or doses of phentermine arespecified, that those amounts or doses refer to the amount or dose ofphentermine per se and not to a phentermine salt or the like. Forexample, when it is indicated that a dose or amount of phentermine is3.75 mg, that would correspond to 4.92 phentermine hydrochloride and not3.75 phentermine hydrochloride.

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, and improvement or remediation of damage. In certainaspects, the term “treating” and “treatment” as used herein refer to theprevention of the occurrence of symptoms. In other aspects, the term“treating” and “treatment” as used herein refer to the prevention of theunderlying cause of symptoms associated with obesity, excess weight,and/or a related condition. The phrase “administering to a subject”refers to the process of introducing a composition or dosage form of theinvention into the subject (e.g., a human or other mammalian subject)via an art-recognized means of introduction

By the terms “effective amount” and “therapeutically effective amount”of an agent, compound, drug, composition or combination of the inventionwhich is nontoxic and effective for producing some desired therapeuticeffect upon administration to a subject or patient (e.g., a humansubject or patient).

The term “dosage form” denotes any form of a pharmaceutical compositionthat contains an amount of active agent sufficient to achieve atherapeutic effect with a single administration. When the formulation isa tablet or capsule, the dosage form is usually one such tablet orcapsule. The frequency of administration that will provide the mosteffective results in an efficient manner without overdosing will varywith the characteristics of the particular active agent, including bothits pharmacological characteristics and its physical characteristics,such as hydrophilicity.

The term “controlled release” refers to a drug-containing formulation orfraction thereof in which release of the drug is not immediate, i.e.,with a “controlled release” formulation, administration does not resultin immediate release of the drug into an absorption pool. The term isused interchangeably with “nonimmediate release” as defined inRemington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton,Pa.: Mack Publishing Company, 1995). In general, the term “controlledrelease” as used herein includes sustained release, modified release anddelayed release formulations.

The term “sustained release” (synonymous with “extended release”) isused in its conventional sense to refer to a drug formulation thatprovides for gradual release of a drug over an extended period of time,and that preferably, although not necessarily, results in substantiallyconstant blood levels of a drug over an extended time period. The term“delayed release” is also used in its conventional sense, to refer to adrug formulation which, following administration to a patient provides ameasurable time delay before drug is released from the formulation intothe patient's body.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. When the term “pharmaceutically acceptable” isused to refer to a pharmaceutical carrier or excipient, it is impliedthat the carrier or excipient has met the required standards oftoxicological and manufacturing testing or that it is included on theInactive Ingredient Guide prepared by the U.S. Food and Drugadministration. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active” (or “active”) derivative or analog, refers toa derivative or analog having the same type of pharmacological activityas the parent compound and approximately equivalent in degree. The term“pharmaceutically acceptable salts” include acid addition salts whichare formed with inorganic acids such as, for example, hydrochloric orphosphoric acids, or such organic acids as acetic, oxalic, tartaric,mandelic, and the like. Salts formed with the free carboxyl groups canalso be derived from inorganic bases such as, for example, sodium,potassium, ammonium, calcium, or ferric hydroxides, and such organicbases as isopropylamine, trimethylamine, histidine, procaine and thelike.

As used herein, “subject” or “individual” or “patient” refers to anysubject for whom or which therapy is desired, and generally refers tothe recipient of the therapy to be practiced according to the invention.The subject can be any vertebrate, but will typically be a mammal. If amammal, the subject will in many embodiments be a human, but may also bea domestic livestock, laboratory subject or pet animal.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described. All publications mentionedherein are incorporated herein by reference to disclose and describe themethods and/or materials in connection with which the publications arecited.

Methods and Formulations of the Invention:

The present invention provides novel methods and compositions to effectweight loss and treat obesity, conditions related to excess weight orobesity, diabetes (whether or not related to obesity), and otherconditions and disorders as will be explained infra. According to theU.S. Centers for Disease Control, the clinical definition of beingoverweight (the term being used synonymously herein with the term“excess weight”) is having a body mass index (BMI) between 25.0 and 29.9kg/m; BMI is calculated by multiplying an individual's weight, inkilograms, by height, in meters. The CDC defines obesity as having a BMIof 30 or higher. In one embodiment, the invention provides a method foreffecting weight loss and treating overweight, obesity, and conditionsassociated with excess weight and obesity, and involves administrationof a combination of the sympathomimetic agent phentermine and theanti-convulsant agent topiramate.

Topiramate is an anticonvulsant sulfamate compound that is sold in theUnited States under the trade name Topamax® (Ortho-McNeilPharmaceutical, Inc., Raritan, N.J., U.S.A). Topiramate has beenapproved for use as an antiepileptic agent as an adjuvant therapy forpatients with partial onset seizures or primary generalized tonic-clonicseizures, and for the prevention of migraine headache. See Physician'sDesk Reference, 56th ed. (2002); see also U.S. Pat. No. 4,513,006 toMaryanoff et al. and U.S. Pat. No. 7,351,695 to Almarssoo et al.

“Topiramate” generally refers to the sulfamate-substitutedmonosaccharide having the chemical name2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate and themolecular formula C12H21NO8S. The structure of the compound isrepresented by Formula (I)

As used herein, the term “topiramate” encompasses2,3,4,5-bis-(O)-(1-methylethylidene)-β-D-fructopyranose sulfamate aswell as individual enantiomers, individual diastereomers, or mixturesthereof. The term “topiramate” as used herein also encompassestopiramate salts as well as polymorphs, solvates (including hydrates andmixed solvates, as well as hydrates of salts), co-crystals (forinstance, with other compounds or other forms of topiramate), amorphous,and anhydrous forms of the compound of Formula (I). Topiramate saltsuseful in conjunction with the present invention, as will be appreciatedfrom the fact that the compound is a sulfamic acid derivative, arepharmaceutically acceptable basic addition salts. Such salts areprepared from bases that provide a pharmaceutically acceptable cationthat associates with the sulfamic acid group of the compound of Formula(I). Suitable pharmaceutically acceptable cations include both organicand inorganic cations, including, without limitation, sodium, sodium,potassium, lithium, magnesium, calcium, aluminum, zinc, procaine,benzathine, chloroprocaine, choline, diethylamine, ethylenediamine,N-methylglucamine, benethamine, clemizole, diethylamine, piperazine,tromethamine, triethylamine, ethanolamine, triethanolamine, arginine,lysine, histidine, tributylamine, 2-amino-2-pentylpropanol,2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane,benzylamine, 2-(dimethylamino)ethanol, barium or bismuth counter ions.Particularly preferred cations are sodium, lithium, and potassium. Otherforms of topiramate referenced above may be prepared using methods knownin the art; see, e.g., U.S. Pat. No. 7,351,695.

At dosages previously believed to be required for therapeutic efficacy,administration of topiramate has been associated with significantadverse effects, as noted above, including, without limitation,dizziness, psychomotor slowing, difficulty with memory, fatigue, andsomnolence. See U.S. Pat. No. 7,351,695, supra, and Physicians' DeskReference, supra.

Phentermine is a sympathomimetic agent that has been used as an appetitesuppressant, but, like topiramate, has been associated with significantadverse effects at doses previously believed to be required forefficacy; these effects are generally associated with thecatecholamine-releasing properties of the drug, including, for instance,tachycardia, elevated blood pressure, anxiety, and insomnia. Phentermineis a shortened version of the compound's chemical name,phenyl-tertiary-butylamine, and is also referred to as2-methyl-1-phenylpropan-2-amine and 2-methyl-amphetamine. Phenterminehas the molecular formula C₁₀H₁₅N, the chemical structure of Formula(II)

and is an achiral primary amine. As such, phentermine may be in the formof either the free base or an acid addition salt prepared with an acidthat yields a pharmaceutically acceptable anion. Suitable acid additionsalts may be prepared from organic acids, e.g., acetic acid, propionicacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and thelike, as well as inorganic acids, e.g., hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, etc. As withtopiramate, phentermine may take on various other forms as well.

It has now been surprisingly discovered that a combination of a lowdaily dose of topiramate and a low daily dose of phentermine iseffective in achieving weight loss, treating obesity, treatingconditions related to overweight and obesity, and addressing otherindications as will be discussed herein. The incidence of adverseeffects previously associated with each active agent is significantlyreduced because of the lowered daily dosage as well as the offsettingeffect each active agent has on the potential adverse effects of theother active agent. Even at the low doses of the present methods,phentermine has anorexient properties (e.g., suppresses appetite) and isanorectic without loss of efficacy or without adverse or undesirableside effects to a subject when administered according to the dosageregimens described herein when the phentermine is administered incombination with topiramate.

The present method for effecting weight loss in a subject involvesadministering a daily dose of phentermine in the range of 2 mg to 8 mg,e.g., 2 mg to 5 mg, in combination with a daily dose of topiramateselected to prevent the loss of effectiveness of phentermine alone. Anexample of a suitable daily dose of topiramate that would prevent theloss of effectiveness of phentermine alone is 15 mg to 50 mg, e.g., 15mg to 25 mg or 17 mg to 23 mg. An exemplary dosage regimen involvesadministration of daily doses of 3.75 mg phentermine and 23 mgtopiramate. Another exemplary dosage regimen involves administration ofdaily doses of 7.5 mg and 46 mg topiramate.

When the topiramate and/or the phentermine are associated withadditional moieties, e.g., are in the form of salts, hydrates, or thelike, the dosage herein refers to the compound per se and does notinclude the associated moieties, e.g., cations, anions, hydrates, etc.Thus, if phentermine hydrochloride is used in the methods andcompositions of the invention, 4.92 mg of phentermine hydrochloride(having a molecular weight of 195.69 g/mol) will be necessary to providethe 3.75 mg daily dose of phentermine (having a molecular weight of149.23 g/mol).

The dosage regimen involves continual, i.e., ongoing, administration,over a significant period of time, e.g., in the range of about 4 weeksto about 67 weeks, depending on the severity of an individual's weightproblem, the amount of weight that should be lost, and the rate at whichweight is lost. Generally, although not necessarily, the combination ofthe active agents is administered orally.

The method of administration can involve simultaneous administration ofthe two active agents, in a single composition or in two discretecompositions each containing one of the active agents. The method ofadministration may also involve administration of the two active agentsat different times of day, with the phentermine generally administeredearlier in the day and the topiramate generally administered later inthe day. Normally, however, the two agents are administeredsimultaneously using one or more dosage forms that provide for immediaterelease of the phentermine and controlled release of the topiramate. Inan exemplary embodiment, the phentermine and topiramate are administeredin a single dosage form that provides for immediate release of thephentermine and sustained release and/or delayed release of thetopiramate.

Examples of compositions that contain a combination of phentermine andtopiramate include, without limitation: (1) 2 mg to 5 mg phentermine and17 mg to 23 mg topiramate; (2) 3.75 mg phentermine and 23 mg topiramate;(3) 3.75 mg phentermine in the form of 4.92 mg phentermine hydrochlorideand 23 mg topiramate; (4) 7.5 mg phentermine and 46 mg topiramate; and(5) 7.5 mg phentermine in the form of 9.84 mg phentermine hydrochlorideand 46 mg topiramate.

These and other compositions of the invention exhibit a lower maximumconcentration (Cmax) of topiramate without decreasing total drugexposure defined by the area under the concentration-time curve (AUC).Further, preferred compositions of the present invention can provide fordelayed, sustained release of topiramate such that the maximum plasmaconcentration (Tmax) is reached 6 to 10, typically 6 to 8, hours afteradministration. As depicted in FIG. 1, drug exposure as measured by AUCfor a controlled release (CR) formulation capsule prepared as describedin Example 1 is the same as that observed with an immediate releasetopiramate (Topamax®) tablet despite a 20% reduction in the Cmax.Therefore, formulations of the invention are capable of reducing theCmax of topiramate, enabling a reduction in side effects withoutcompromising the efficacy of the treatment, since the AUC is the same.This reduction in Cmax is preferred as topiramate can be sedating, asnoted above, and a delay in the time to reach maximum plasmaconcentration to the late afternoon or evening time improves thetolerability of the drug. On the other hand, the preferred formulationsof the invention provide for immediate release of phentermine, with themedication administered early in the day, such that any stimulanteffects that may be experienced do not occur in the evening.

In another embodiment of the invention, a composition is provided thatcontains 7.5 mg phentermine and 46 mg topiramate.

Depending on the intended mode of administration, the pharmaceuticalformulation may be a solid, semi-solid or liquid, such as, for example,a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, asuppository, granules, pellets, beads, a powder, or the like, preferablyin unit dosage form suitable for single administration of a precisedosage. Suitable pharmaceutical compositions and dosage forms may beprepared using conventional methods known to those in the field ofpharmaceutical formulation and described in the pertinent texts andliterature, e.g., in Remington: The Science and Practice of Pharmacy(Easton, Pa.: Mack Publishing Co., 1995). Oral administration andtherefore oral dosage forms are generally preferred, and includetablets, capsules, caplets, solutions, suspensions and syrups, and mayalso comprise a plurality of granules, beads, powders, or pellets thatmay or may not be encapsulated. Preferred oral dosage forms are capsulesand tablets, particularly controlled release capsules and tablets, asnoted above.

As noted above, it is especially advantageous to formulate compositionsof the invention in unit dosage form for ease of administration anduniformity of dosage. The term “unit dosage forms” as used herein refersto physically discrete units suited as unitary dosages for theindividuals to be treated. That is, the compositions are formulated intodiscrete dosage units each containing a predetermined, “unit dosage”quantity of an active agent calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. The specifications of unit dosage forms of the invention aredependent on the unique characteristics of the active agent to bedelivered. Dosages can further be determined by reference to the usualdose and manner of administration of the ingredients. It should be notedthat, in some cases, two or more individual dosage units in combinationprovide a therapeutically effective amount of the active agent, e.g.,two tablets or capsules taken together may provide a therapeuticallyeffective dosage of topiramate, such that the unit dosage in each tabletor capsule is approximately 50% of the therapeutically effective amount.

Tablets may be manufactured using standard tablet processing proceduresand equipment. Direct compression and granulation techniques arepreferred. In addition to the active agent, tablets will generallycontain inactive, pharmaceutically acceptable carrier materials such asbinders, lubricants, disintegrants, fillers, stabilizers, surfactants,coloring agents, and the like.

Capsules are also preferred oral dosage forms, in which case the activeagent-containing composition may be encapsulated in the form of a liquidor solid (including particulates such as granules, beads, powders orpellets). Suitable capsules may be either hard or soft, and aregenerally made of gelatin, starch, or a cellulosic material, withgelatin capsules preferred. Two-piece hard gelatin capsules arepreferably sealed, such as with gelatin bands or the like. See, forexample, Remington: The Science and Practice of Pharmacy, cited earlierherein, which describes materials and methods for preparing encapsulatedpharmaceuticals.

Oral dosage forms, whether tablets, capsules, caplets, or particulates,can, if desired, be formulated so as to provide for controlled releaseof topiramate, and in a preferred embodiment, the present formulationsare controlled release oral dosage forms. Generally, the dosage formsprovide for sustained release, i.e., gradual, release of topiramate,from the dosage form to the patient's body over an extended time period,typically providing for a substantially constant blood level of theagent over a time period in the range of about 4 to about 12 hours,typically in the range of about 6 to about 10 hours or 6 to about 8hours. Release of the topiramate may also be delayed; that is, there isa time lag between administration and the start of topiramate release.In this way, for instance, an individual will not experience sleepinessor other side effects of topiramate during the school or work day.Preferred dosage forms thus involve sustained release of the topiramate,delayed release of the topiramate, or both sustained and delayed releaseof the topiramate.

Generally, as will be appreciated by those of ordinary skill in the art,sustained release dosage forms can be formulated by dispersing theactive agent within a matrix of a gradually hydrolyzable material suchas a hydrophilic polymer, or by coating a solid, drug-containing dosageform with such a material. Hydrophilic polymers useful for providing asustained release coating or matrix include, by way of example:cellulosic polymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethylcellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylicacid polymers and copolymers, preferably formed from acrylic acid,methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkylesters, and the like, e.g. copolymers of acrylic acid, methacrylic acid,methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethylmethacrylate; and vinyl polymers and copolymers such as polyvinylpyrrolidone e.g., Povidone K30, polyvinyl acetate, and ethylene-vinylacetate copolymer. Preferred sustained release polymers herein includethose available as “Methocel” polymers from Dow Chemical, particularlythe methylcellulose ether polymers in the Methocel™ A group, having aviscosity grade of about 4,000 cps and a methoxyl content of about 27.5%to 31.5%, e.g., Methocel™ A15LV, Methocel™ A15C, and Methocel™ A4M.

When sustained release preparations are prepared, tablets, granules,powder, capsules, and the like can be produced according to aconventional method after adding excipient, and as necessary, binder,disintegrating agent, lubricant, coloring agent, taste-modifying agent,flavoring agent, and the like. These additives may be ones generallyused in the field, and for example, lactose, sodium chloride, glucose,starch, microcrystalline cellulose, and silicic acid as the excipient,water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropylcellulose, methyl cellulose, ethyl cellulose, shellac, calciumphosphate, and polyvinylpyrrolidone as the binder, agar powder, sodiumhydrogen carbonate, sodium lauryl sulfate, and stearic acidmonoglyceride as the disintegrating agent, purified talc, stearic acidsalt, borax, and polyethylene glycol as the lubricant, β-carotene,yellow iron sesquioxide, and caramel as the coloring agent, andsaccharose and orange peel as the taste-modifying agent can be listed asexamples. It should be noted that various grades of microcrystallinecellulose are preferred fillers herein, e.g., Avicel® PH101, Avicel®PH102, and Avicel® PH200 (FMC), with particle sizes of about 50 microns,100 microns, and 190 microns, respectively. Microcrystalline cellulosehaving a particle size in the range of about 50 microns to 200 micronsis preferred herein.

The dosage forms may also be provided with a delayed release coating,e.g., composed of an acrylate and/or methacrylate copolymers. Examplesof such polymers are those available under the trade name “Eudragit”from Rohm Pharma (Germany). The Eudragit series E, L, S, RL, RS, and NEcopolymers are available as solubilized in organic solvent, in anaqueous dispersion, or as a dry powder. Preferred acrylate polymers arecopolymers of methacrylic acid and methyl methacrylate, such as theEudragit L and Eudragit S series polymers. Other preferred Eudragitpolymers are cationic, such as the Eudragit E, RS, and RL seriespolymers. Eudragit E100 and E PO are cationic copolymers ofdimethylaminoethyl methacrylate and neutral methacrylates (e.g., methylmethacrylate), while Eudragit RS and Eudragit RL polymers are analogouspolymers, composed of neutral methacrylic acid esters and a smallproportion of trimethylammonioethyl methacrylate.

In a specific embodiment, controlled release topiramate beads for oraladministration, e.g., by incorporation in an orally administrablecapsule or compaction into an orally administrable tablet, are madeusing an extrusion spheronization process to produce a matrix corecomprised of: topiramate, 40.0% w/w; microcrystalline cellulose, e.g.,Avicel® PH102, 56.5% w/w; and methylcellulose, e.g., Methocel™ A15 LV,3.5% w/w. The topiramate cores are then coated with ethyl cellulose,5.47% w/w and Povidone K30: 2.39% w/w. The phentermine beads arecomposed of an immediate release drug coating onto sugar spheres oranalogous non-active cores. Both sets of beads may then be encapsulatedinto one capsule.

Preparations according to this invention for parenteral administrationinclude sterile aqueous and nonaqueous solutions, suspensions, andemulsions. Injectable aqueous solutions contain the active agent inwater-soluble form. Examples of nonaqueous solvents or vehicles includefatty oils, such as olive oil and corn oil, synthetic fatty acid esters,such as ethyl oleate or triglycerides, low molecular weight alcoholssuch as propylene glycol, synthetic hydrophilic polymers such aspolyethylene glycol, liposomes, and the like. Parenteral formulationsmay also contain adjuvants such as solubilizers, preservatives, wettingagents, emulsifiers, dispersants, and stabilizers, and aqueoussuspensions may contain substances that increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, anddextran. Injectable formulations are rendered sterile by incorporationof a sterilizing agent, filtration through a bacteria-retaining filter,irradiation, or heat. They can also be manufactured using a sterileinjectable medium. The active agent may also be in dried, e.g.,lyophilized, form that may be rehydrated with a suitable vehicleimmediately prior to administration via injection.

The active agents may also be administered through the skin usingconventional transdermal drug delivery systems, wherein the active agentis contained within a laminated structure that serves as a drug deliverydevice to be affixed to the skin. In such a structure, the drugcomposition is contained in a layer, or “reservoir,” underlying an upperbacking layer. The laminated structure may contain a single reservoir,or it may contain multiple reservoirs. In one embodiment, the reservoircomprises a polymeric matrix of a pharmaceutically acceptable contactadhesive material that serves to affix the system to the skin duringdrug delivery. Alternatively, the drug-containing reservoir and skincontact adhesive are present as separate and distinct layers, with theadhesive underlying the reservoir which, in this case, may be either apolymeric matrix as described above, or it may be a liquid or hydrogelreservoir, or may take some other form. Transdermal drug deliverysystems may in addition contain a skin permeation enhancer.

In addition to the formulations described previously, the active agentmay be formulated as a depot preparation for controlled release of theactive agent, preferably sustained release over an extended time period.These sustained release dosage forms are generally administered byimplantation (e.g., subcutaneously or intramuscularly or byintramuscular injection).

Although the present compositions will generally be administered orally,parenterally, transdermally, or via an implanted depot, other modes ofadministration are suitable as well. For example, administration may betransmucosal, e.g., rectal or vaginal, preferably using a suppositorythat contains, in addition to the active agent, excipients such as asuppository wax. Formulations for nasal or sublingual administration arealso prepared with standard excipients well known in the art. Thepharmaceutical compositions of the invention may also be formulated forinhalation, e.g., as a solution in saline, as a dry powder, or as anaerosol.

Indications:

Conditions of particular interest for which the invention finds utilityinclude overweight, obesity and conditions often associated with and/orcaused by excess weight and obesity. The combination of topiramate andphentermine in the dosages provided herein give rise to significanttherapeutic effects and reduced adverse effects, making thesepharmaceutical combinations extremely effective therapeutics, especiallyin the treatment of overweight, obesity and/or related conditions,including conditions associated with and/or caused by excess weight orobesity per se. Subjects suitable for treatment with the subjectcombination therapy treatment regimen thus include individuals sufferingfrom conditions associated with obesity, such conditions including,without limitation:

diabetes, insulin resistance, and impaired glucose tolerance;

respiratory problems such as pulmonary hypertension, asthma, andshortness of breath;

gallbladder disease;

dyslipidemia, e.g., high cholesterol, high levels of triglycerides,etc.;

osteoarthritis and other orthopedic problems;

reflux esophagitis;

adverse conditions related to sleep, including sleep apnea and loudsnoring;

menstrual irregularities, infertility, and complications in pregnancy;

gout;

high blood pressure, i.e., hypertension;

cardiovascular problems such as coronary artery disease and other hearttrouble;

muscular dystrophy;

stroke, particularly thrombotic stroke and deep vein thrombosis (DVT);

migraines;

metabolic disorders such as hypoalphalipoproteinemia, familial combinedhyperlipidemia, and Syndrome X, including insulin-resistant Syndrome X;and

colon, rectal, renal, esophageal, gallbladder, pancreatic, prostate,breast, uterine, ovarian, endometrial, and cervical cancers.

Higher body weights are also associated with increases in all-causemortality. Most or all of these problems are relieved or improved bypermanent significant weight loss. Longevity is likewise significantlyincreased by permanent significant weight loss.

Diabetes mellitus is very commonly seen in obese individuals, and isassociated with continuous and pathologically elevated blood glucoseconcentration. It is one of the leading causes of death in the UnitedStates and is responsible for about 5% of all mortality. Diabetes isdivided into two major sub-classes: Type I, also known as juvenilediabetes, or Insulin-Dependent Diabetes Mellitus (IDDM); and Type II,also known as adult onset diabetes, or Non-Insulin-Dependent DiabetesMellitus (NIDDM).

According to the American Diabetes Association, there are over onemillion juvenile diabetics in the United States. Type I Diabetes is aform of autoimmune disease. Autoantibodies produced by the patientscompletely or partially destroy the insulin producing cells of thepancreas. Juvenile diabetics must, therefore, receive exogenous insulinduring their lifetime. Without treatment, excessive acidosis,dehydration, kidney damage, and death may result. Even with treatment,complications such as blindness, atherosclerosis, and impotence canoccur.

There are more than five million Type II (adult onset) diabeticsdiagnosed in the United States. Type II disease usually begins duringmiddle age; the principal cause is now known to be overweight andobesity. In Type II diabetics, rising blood glucose levels after mealsdo not properly stimulate insulin production by the pancreas.Additionally, peripheral tissues are generally resistant to the effectsof insulin. The resulting high blood glucose levels (hyperglycemia) cancause extensive tissue damage. Type II diabetics are often referred toas insulin resistant. They often have higher than normal plasma insulinlevels (hyperinsulinemia) as the body attempts to overcome its insulinresistance. Some researchers now believe that hyperinsulinemia may be acausative factor in the development of high blood pressure, high levelsof circulating low density lipoproteins (LDLs), and lower than normallevels of the beneficial high density lipoproteins (HDLs). Whilemoderate insulin resistance can be compensated for in the early stagesof Type II diabetes by increased insulin secretion, in more advanceddisease states insulin secretion is also impaired.

Insulin resistance and hyperinsulinemia have also been linked with twoother metabolic disorders that pose considerable health risks: impairedglucose tolerance and metabolic obesity. Impaired glucose tolerance ischaracterized by normal glucose levels before eating, with a tendencytoward elevated levels (hyperglycemia) following a meal. According tothe World Health Organization, approximately 11% of the U.S. populationbetween the ages of 20 and 74 are estimated to have impaired glucosetolerance. These individuals are considered to be at higher risk fordiabetes and coronary artery disease.

Obesity may also be associated with insulin resistance. A causal linkageamong obesity, impaired glucose tolerance, and Type II diabetes has beenproposed, but a physiological basis has not yet been established. Someresearchers believe that impaired glucose tolerance and diabetes areclinically observed and diagnosed only later in the disease processafter a person has developed insulin resistance and hyperinsulinemia.

Insulin resistance is frequently associated with hypertension, coronaryartery disease (arteriosclerosis), and lactic acidosis, as well asrelated disease states. The fundamental relationship between thesedisease states, and a method of treatment, has not been established.

Hypertension is another condition that is frequently seen in obeseindividuals, and occurs when the blood pressure inside the largearteries is chronically elevated. Hypertension affects about 50 millionpeople in the United States alone. It is more common as people growolder and is both more common and more serious in African Americans.Most cases of hypertension are of unknown etiology. It is known that thetendency to develop hypertension can be inherited. Environment alsoplays a very important role in hypertension. For example, hypertensionmay be avoided by keeping body weight under control, keeping physicallyfit, eating a healthy diet, limiting alcohol intake, and avoidingmedications that might increase blood pressure. Other less common causesof hypertension include disorders of the kidneys or endocrine glands.Hypertension has been called “the silent killer” because it has nospecific symptoms and yet can lead to death. People with untreatedhypertension are much more likely to die from or be disabled bycardiovascular complications such as strokes, heart attacks, heartfailure, heart rhythm irregularities, and kidney failure, than peoplewho have normal blood pressure.

Current treatments for hypertension include lifestyle changes (diet,exercise, nonsmoking, etc.) as well as drug therapy. The major classesof medications currently used to treat hypertension include adrenergicneuron antagonists (which are peripherally acting), alpha adrenergicagonists (which are centrally acting), alpha adrenergic blockers, alphaand beta blockers, angiotensin II receptor blockers, angiotensinconverting enzyme (ACE) inhibitors, beta adrenergic blockers, calciumchannel blockers, thiazides (benzothiadiazine derivatives) and relateddiuretics, and vasodilators (which act by direct relaxation of vascularsmooth muscles).

A particularly serious hypertensive disorder is primary pulmonaryhypertension, also known as idiopathic pulmonary hypertension. This is acondition in which the blood pressure in the pulmonary arteries isabnormally high in the absence of other diseases of the heart or lungs.The cause of primary pulmonary hypertension is unknown. Pulmonaryhypertension develops in response to increased resistance to blood flow.Narrowing of the pulmonary arterioles occurs and the right side of theheart becomes enlarged due to the increased work of pumping bloodagainst the resistance. Eventually, progressive heart failure develops.Currently, there is no known cure for primary pulmonary hypertension.Treatment is primarily directed towards controlling the symptoms,although some success has occurred with the use of vasodilators. Othermedications used to treat the symptoms of primary pulmonary hypertensioninclude diuretics and calcium channel blockers. Typically, as thedisease progresses, oxygen is often required. In certain cases, aheart-lung transplant may be indicated for certain suitable candidates,although the availability of donor organs continues to be extremelylimited. Unfortunately, primary pulmonary hypertension is a progressivedisease, usually leading to congestive heart failure and respiratoryfailure.

Secondary pulmonary hypertension is a serious disorder that arises as acomplication of other conditions such as, for example, scleroderma.Treatments are similar as those for primary pulmonary hypertension and,unfortunately, the prognosis is the same as well.

Other respiratory disorders that are frequently seen in obeseindividuals include asthma and shortness of breath, both of whichconditions are often alleviated by weight loss.

With respect to adverse conditions and disorders associated with sleep,sleep apnea is perhaps the most concerning. Sleep apnea is classified aseither obstructive sleep apnea, the more common form that occurs whenthroat muscles relax, or central sleep apnea, which occurs when thebrain doesn't send proper signals to the muscles that control breathing.Additionally, some people have mixed sleep apnea, which is a combinationof both obstructive and central sleep apneas. Sleep apnea literallymeans “cessation of breath.” It is characterized by repetitive episodesof upper airway obstruction that occur during sleep, usually associatedwith a reduction in blood oxygen saturation. In other words, the airwaybecomes obstructed at several possible sites. The upper airway can beobstructed by excess tissue in the airway, large tonsils, and a largetongue and usually includes the airway muscles relaxing and collapsingwhen asleep. Another site of obstruction can be the nasal passages.Sometimes the structure of the jaw and airway can be a factor in sleepapnea.

The signs and symptoms of obstructive and central sleep apneas overlap,sometimes making the type of sleep apnea more difficult to determine.The most common signs and symptoms of obstructive and central sleepapneas include: excessive daytime sleepiness (hypersomnia); loudsnoring; observed episodes of breathing cessation during sleep; abruptawakenings accompanied by shortness of breath; awakening with a drymouth or sore throat; morning headache; and/or difficulty staying asleep(insomnia). Disruptive snoring may be a more prominent characteristic ofobstructive sleep apnea, while awakening with shortness of breath may bemore common with central sleep apnea.

Sleep apnea is a progressive condition and can be very serious; it is apotentially life-threatening condition that requires immediate medicalattention. The risks of undiagnosed obstructive sleep apnea includeheart attacks, strokes, high blood pressure, heart disease, irregularheartbeat, and impotence. In addition, obstructive sleep apnea causesdaytime sleepiness that can result in accidents, lost productivity andinterpersonal relationship problems. The severity of the symptoms may bemild, moderate or severe.

Sleep apnea is diagnosed utilizing a sleep test, called polysomnographybut treatment methodologies differ depending on the severity of thedisorder. Mild Sleep Apnea is usually treated by some behavioralchanges; losing weight and sleeping on one's side are often recommended.There are oral mouth devices (that help keep the airway open) that mayhelp to reduce snoring in three different ways. Some devices (1) bringthe jaw forward or (2) elevate the soft palate or (3) retain the tongue(from falling back in the airway and blocking breathing).

Moderate to severe sleep apnea is usually treated with a continuouspositive airway pressure (C-PAP). C-PAP is a machine that blows air intoyour nose via a nose mask, keeping the airway open and unobstructed. Formore severe apnea, there is a Bi-level (Bi-PAP) machine. The Bi-levelmachine is different in that it blows air at two different pressures.When a person inhales, the pressure is higher and in exhaling, thepressure is lower.

Some people have facial deformities that may cause the sleep apnea. Itsimply may be that their jaw is smaller than it should be or they couldhave a smaller opening at the back of the throat. Some people haveenlarged tonsils, a large tongue or some other tissues partiallyblocking the airway. Fixing a deviated septum may help to open the nasalpassages. Removing the tonsils and adenoids or polyps may help also.Children are much more likely to have their tonsils and adenoidsremoved. Surgical procedures, such as tracheotomy,uvulopalatopharyngoplasty (UPPP), laser assisted uvuloplasty (LAUP),somnoplasty, and mandibular myotomy are often required to effectivelytreat sleep apnea. Weight loss, however, particularly in an obeseperson, can significantly alleviate sleep apnea and other sleep-relatedadverse conditions such as loud snoring and the like.

Relatively recently, a connection between obesity and the occurrence orincreased incidence of migraine headaches has been noted. Migraineheadaches begin with mild pain, which increases in intensity over ashort period of time. There are two major types of migraines. The commonmigraine affects 80-85% of migraine sufferers and classical migrainewith aura affects 15% of migraine sufferers. Symptoms associated withmigraines include headaches, psychological symptomology such asirritability, depression, fatigue, drowsiness, restlessness;neurological symptoms such as photophobia, phonophobia orgastrointestinal symptoms such as change in bowel habit, change of foodintake or urinary symptoms such as urinary frequency, auras which areneurological deficits and can be a variety of deficits for the migrainepopulation but in the individual is usually stereotyped. These deficitsmay be visual scotoma or visual designs, hemiplegia, migratingparaesthesia, dysarthria, dysphasia, or déjà vu. The headache is usuallyaccompanied by light or sound sensitivity, photophobia or phonophobia,irritability and impaired concentration. For those individuals whosemigraine headaches are caused by or exacerbated by obesity, treatmentaccording to the methodology of the present invention can be effective.

Other indications for which the present invention is readily adaptedinclude epilepsy and certain psychiatric indications such as impulsecontrol disorders.

Topiramate has long been known as an anti-epileptic agent. At dosagespreviously required or believed to be required for efficacy, however,topiramate therapy resulted in significant side effects, as notedelsewhere herein. The present invention, according to which topiramatedosage may be reduced by concomitant administration of phentermine,significantly reduces those side effects of topiramate, most if not allof which are dose-related.

Among psychiatric indications, depression is particularly common.“Depression,” as is well known, is manifested by a combination ofsymptoms that interfere with the ability to work, study, sleep, eat, andenjoy once pleasurable activities. Depression includes major depression,especially refractory depression, bipolar depression, and thedegeneration associated with depression. Symptoms of depression includepersistent sad, anxious, or “empty” mood, feelings of hopelessness,pessimism, feelings of guilt, worthlessness, helplessness, loss ofinterest or pleasure in hobbies and activities that were once enjoyed,including sex, decreased energy, fatigue, being “slowed down”,difficulty concentrating, remembering, making decisions, insomnia,early-morning awakening, or oversleeping, appetite and/or weight loss orovereating and weight gain, thoughts of death or suicide; suicideattempts, restlessness, irritability, persistent physical symptoms thatdo not respond to treatment, such as headaches, digestive disorders, andchronic pain.

Other psychiatric disorders may also be treated using the compositionsand methods of the invention. These disorders include impulse controldisorders, panic syndrome, general anxiety disorder, phobic syndromes ofall types, mania, manic depressive illness, hypomania, unipolardepression, stress disorders, PTSD, somatoform disorders, personalitydisorders, psychosis, and schizophrenia.

“Impulse Control Disorders” are characterized by harmful behaviorsperformed in response to irresistible impulses. The essential feature ofan impulse control disorder is the failure to resist an impulse, drive,or temptation to perform an act that is harmful to the person or toothers. Symptoms include an increasing sense of tension or arousalbefore committing an act, and then experiences pleasure, gratification,or release at the time of committing the act. After the act isperformed, there may or may not be regret or guilt. Numerous disorderscan be characterized as impulse control disorders including intermittentexplosive disorder, kleptomania, pathological gambling, pyromania,trichotillomania, compulsive buying or shopping, repetitiveself-mutilation, nonparaphilic sexual addictions, severe nail biting,compulsive skin picking, personality disorders with impulsive features,attention deficit/hyperactivity disorder, eating disorders characterizedby binge eating, and substance abuse disorders such as alcoholism anddrug addiction. Binge eating disorder and bulimia are also sometimesclassified as impulse control disorders.

Packaged Pharmaceutical Preparations:

Also provided are packaged pharmaceutical preparations for practicingthe subject methods. The packaged preparation contains a composition ofthe invention in a sealed container, and typically contains a pluralityof individual dosage forms each in a sealed housing, as in a blisterpack, but could also contain one or more dosage forms in a single sealedcontainer. The dosage forms might be, for instance, dosage formscontaining 3.75 mg phentermine in immediate release form and 23 mgtopiramate in controlled release form, or, in an alternative example,7.5 mg phentermine in immediate release form and 46 mg topiramate incontrolled release form. Optionally, dosage forms with lower doses ofone or both active agents can also be included, for dose titration anddose escalation.

In certain embodiments, the packaged pharmaceutical preparations includeinstructions for a patient to carry out drug administration to achieveweight loss, treat obesity, treat conditions associated with obesity, ortreat other conditions as explained earlier herein. For instance, theinstructions may include the daily dose of topiramate to be taken, thedaily dose of phentermine to be taken, and/or the dosing regimen forself-administration of a controlled release dosage form containing bothactive agents. The instructions may be recorded on a suitable recordingmedium or printed on a substrate such as paper or plastic. As such, theinstructions may be present as a package insert, in the labeling of thepackage, container(s), or components thereof (i.e., associated with thepackaging or sub-packaging), etc. In other embodiments, the instructionsare present as an electronic storage data file present on a suitablecomputer readable storage medium, e.g. CD-ROM, diskette, etc. In yetother embodiments, the actual instructions are not present, but meansfor obtaining the instructions from a remote source, e.g. via theinternet, are provided. As an example, a web address might be includedto direct patients to a website where the instructions can be viewedand/or from which the instructions can be downloaded. As with theinstructions per se, this means for obtaining the instructions isrecorded on a suitable substrate.

Some or all of the included components may be packaged in suitablepackaging to maintain sterility. In many embodiments, the components arepackaged in a containment element to provide a single, easily handledunit, where the containment element, e.g., box or analogous structure,may or may not be an airtight container, e.g., to further preserve thesterility of some or all of the components. In certain aspects, a sealedpackage of controlled release dosage forms is provided wherein thedosage forms contain phentermine in immediate release form andtopiramate in controlled release, e.g., sustained release and delayedrelease form. Alternatively, separate phentermine-containing andtopiramate-containing dosage forms may be included.

This invention is further illustrated by the following examples whichshould not be construed as limiting. Although any methods and materialssimilar or equivalent to those described herein may be useful in thepractice or testing of the present invention, preferred methods andmaterials are described below.

The contents of all references, patents and published patentapplications cited throughout this application are hereby incorporatedby reference.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Celsius, andpressure is at or near atmospheric.

Example 1

Controlled release topiramate beads are made using an extrusionspheronization process to produce a matrix core comprised of topiramate,40.0% w/w; microcrystalline cellulose (Avicel® PH102), 56.5% w/w; andMethocel™ A15 LV, 3.5% w/w. The topiramate cores were then coated withethyl cellulose, 5.47% w/w, and Povidone K30, 2.39% w/w.

The composition of the topiramate beads so prepared is as follows:

Component % w/w topiramate 36.85 microcrystalline cellulose, 52.05(Avicel ® PH102) Methylcellulose 3.22 (Methocel ™ A15 LV) ethylcellulose5.47 Polyvinylpyrrolidone 2.39 (Povidone K30)

Phentermine hydrochloride is coated onto sugar spheres to provideimmediate release phentermine beads. Both sets of beads are thenencapsulated into each of a plurality of capsules, with each capsulecontaining 3.75 mg phentermine (as 4.92 mg phentermine HCl) and 23 mgtopiramate.

Example 2

Controlled release topiramate beads and immediate release phenterminebeads are prepared as in Example 1. Both sets of beads are thenencapsulated into each of a plurality of capsules, with each capsulecontaining 7.5 mg phentermine and 46 mg topiramate.

Example 3

In a study comparing controlled-release formulation of topiramateaccording to the present invention versus immediate release topiramate(Topamax®) in combination with phentermine, the controlled releaseformulation of the instant invention of topiramate had a 10-15% lowereffect on phentermine exposure (FIG. 2).

The mean and statistical comparisons for plasma phentermine PKparameters at steady state in multiple dose administrations aresummarized in Table 1.

TABLE 1 Arithmetic Mean (SD) and Statistical Comparison ofPharmacokinetic Parameters for Plasma Phentermine Treatment 2 VersusTreatment 4 Mean +/− SD 90% Pharmacokinetic Treatment 2 Treatment 4Confidence Parameters (N = 13) (N = 12) Intervals % Mean RatioAUC_(0-tau) 2250 +/− 563  2530 +/− 644  (75.6, 105.3) 89.2 (ng * hr/mL)AUC₀₋₉₆ 4640 +/− 1570 5550 +/− 1960 (67.1, 105.0) 84.0 (ng * hr/mL)AUC_(0-t) 4640 +/− 1570 5550 +/− 1960 (67.1, 105.0) 84.0 (ng * hr/mL)C_(max,ss)  114 +/− 23.6  127 +/− 27.6 (78.8, 104.5) 90.7 (ng * hr/mL)C_(min,ss) (ng * hr/mL) 9.84 +/− 7.24 14.6 +/− 11.3 (42.5, 109.0) 68.1t_(max) (hr) 4.01 (1.04, 7.00) 4.54 (1.00, 10.0) T_(1/2) (hr) 23.3 +/−6.17 26.3 +/− 7.43 CL_(ss)/F (L/hr) 7.10 +/− 1.89 6.38 +/− 2.00 V₂/F(L/hr)  229 +/− 45.3  232 +/− 58.5 t_(max) is presented as median(minimum, maximum) Parameters were dose-normalized and In-transformedprior to analysis. % Mean Ratio = 100 * ex[(Treatment 2 − Treatment 4)for In-transformed parameters Treatment 1 (Test): 7.5 mg phentermine/50mg topiramate (Formulation A) Treatment 2 (Test): 15 mg phentermine/100mg topiramate (Formulation A) Treatment 4 (Reference): 15 mgphentermine/100 mg topiramate Source: Tables 14.2.1.8, 14.2.1.10,14.2.1.12, and 14.2.1.17

These data indicate a lower maximum and extent of phentermine exposurebetween tests versus reference treatments after multiple-doseadministration. As such, the controlled release formulation oftopiramate reduced drug interaction with phentermine which in turn willreduce further side effects associated with phentermine.

Example 4

A patient with obesity and elevated lipids exhibiting a heart murmur,shortness of breath out of proportion to weight and age, low bloodpressure, leg edema, and a BMI of 46 undergoes an echocardiogram, whichshows mitral regurgitation of 1-2+ and mild elevation in pulmonaryartery pressure of 36 mm

The composition prepared in Example 1 is administered to the patient ona daily basis, and the patient additionally proceeds with a low fat, lowcarbohydrate diet and daily exercise. Two weeks after the start of herweight loss program she reports that her exercise tolerance is markedlyimproved and previous chest pressure and shortness of breath on exertionare gone. The patient loses weight continuously on the program and afterfour months can be expected to lose at least 20 pounds. Ongoingcontinuation of the program can be expected to result in further weightloss and additional improvement in obesity-related conditions.

Example 5

The procedure of Example 4 is repeated with a second patient having aBMI over 40 and suffering from similar conditions related to obesity.

The composition prepared in Example 2 is administered to the patient ona daily basis, and the patient additionally proceeds with a low fat, lowcarbohydrate diet and daily exercise. Two weeks after the start of hisweight loss program he reports that her exercise tolerance is markedlyimproved. The patient loses weight continuously on the program and afterfour months can be expected to lose at least 25 pounds. Ongoingcontinuation of the program can be expected to result in further weightloss and additional improvement in obesity-related conditions.

The invention claimed is:
 1. A unit dosage form for weight loss for oraladministration to a patient having a body mass index of at least 25kg/m², comprising a combination of: an immediate release phentermineformulation containing a unit dosage of phentermine of 3.75 mg or 7.5mg; and a controlled release topiramate formulation containing a unitdosage of topiramate of 23 mg or 46 mg, wherein the controlled releasetopiramate formulation reaches a maximum plasma concentration (Cmax) atabout 6 to about 10 hours (Tmax) after administration.
 2. The dosageform of claim 1, wherein the subject is overweight having a body massindex between 25 kg/m² and 29.9 kg/m².
 3. The dosage form of claim 2,wherein the subject has a condition associated with obesity.
 4. Thedosage form of claim 1, wherein the subject is obese having a body massindex of at least 30 kg/m².
 5. The dosage form of claim 4, wherein thecondition associated with obesity is selected from the group consistingof diabetes, elevated fasting blood glucose, insulin resistance,impaired glucose tolerance, pulmonary hypertension, asthma, shortness ofbreath, gallbladder disease, dyslipidemia, high cholesterol, high levelsof triglycerides, osteoarthritis, reflux esophagitis, sleep apnea,menstrual irregularities, infertility, complications in pregnancy, gout,high blood pressure, hypertension, coronary artery disease, heartdisease, muscular dystrophy, stroke, thrombotic stroke, deep veinthrombosis (DVT), migraines, metabolic disorders,hypoalphalipoproteinemia, familial combined hyperlipidemia, Syndrome X,insulin-resistant Syndrome X, colon cancer, rectal cancer, renal cancer,esophageal cancer, gallbladder cancer, pancreatic cancer, prostatecancer, breast cancer, uterine cancer, ovarian cancer, endometrialcancer, and cervical cancer.
 6. The dosage form of claim 3, wherein thecondition associated with obesity is selected from the group consistingof hypertension, dyslipidemia, and type 2 diabetes mellitus.
 7. Thedosage form of claim 3, wherein the subject is suffering from at leasttwo conditions associated with obesity selected from the groupconsisting of hypertension, dyslipidemia, and type 2 diabetes mellitus.8. The dosage form of claim 1, wherein the topiramate formulated forcontrolled release further exhibits a lower Cmax, than non-controlledrelease topiramate, without decreasing total drug exposure defined bythe area under the concentration-time curve (AUC).
 9. The dosage form ofclaim 1, wherein the unit dosage of phentermine is 3.75 mg and the unitdosage of topiramate is 23 mg.
 10. The dosage form of claim 9, whereinthe 3.75 mg phentermine is provided in the unit dosage form as about4.92 mg phentermine hydrochloride, and wherein 4.92 mg of phenterminehydrochloride provides 3.75 mg of phentermine.
 11. The dosage form ofclaim 1, wherein the unit dosage of phentermine is 7.5 mg and the unitdosage of topiramate is 46 mg.
 12. The dosage form of claim 11, whereinthe 7.5 mg phentermine is provided in the unit dosage form as about 9.84mg phentermine hydrochloride, and wherein 9.84 mg of phenterminehydrochloride provides 7.5 mg of phentermine.
 13. The dosage form ofclaim 1, wherein following oral administration to a patient, the dosageform provides for a substantially constant blood level of topiramateover a time period in the range of about 4 to about 12 hours.
 14. Thedosage form of claim 13, wherein the time period is in the range ofabout 6 to about 10 hours.
 15. The dosage form of claim 1, wherein thecontrolled release topiramate formulation reaches a maximum plasmaconcentration at about 8 hours to about 10 hours (Tmax) afteradministration.
 16. The dosage form of claim 1, wherein the immediaterelease phentermine formulation comprises beads of inactive cores coatedwith the immediate release phentermine formulation.
 17. The dosage formof claim 16, comprising a capsule housing the immediate releasephentermine beads and the controlled release topiramate beads.
 18. Thedosage form of claim 1, wherein the controlled release topiramateformulation comprises beads comprising a core comprising topiramatedispersed in a gradually hydrolysable material comprising a binder, anda polymeric filler, and wherein the core is provided with a delayedrelease coating.
 19. The dosage form of claim 18, wherein the delayedrelease coating comprises one or more of ethylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, hydroxypropyl cellulose,polyvinyl acetate, ethylene-vinyl acetate copolymer and polyvinylpyrrolidone.
 20. The dosage form of claim 18, wherein the delayedrelease coating comprises ethylcellulose and polyvinyl pyrrolidone. 21.The dosage form of claim 18, wherein the polymeric filler comprisesmicrocrystalline cellulose.
 22. The dosage form of claim 21, wherein themicrocrystalline cellulose has a particle size of 50 microns to 200microns.
 23. The dosage form of claim 18, wherein the binder comprisesmethylcellulose.
 24. The dosage form of claim 20, wherein the ethylcellulose and the polyvinyl pyrrolidone in the delayed release coatingare in a weight ratio of approximately 2.3:1.
 25. The dosage form ofclaim 1, comprising a tablet with at least two discrete segments, atleast one of which contains the immediate release phentermineformulation and at least another of which contains the controlledrelease topiramate formulation.
 26. The dosage form of claim 1, whereinthe controlled release topiramate formulation comprises beads comprisingtopiramate dispersed within a delayed release matrix comprisingmethylcellulose, microcrystalline cellulose, ethylcellulose andpolyvinyl pyrrolidine.
 27. The dosage form of claim 1, wherein thecontrolled release topiramate formulation comprises beads comprisingtopiramate dispersed within a delayed release matrix comprisinghydroxypropyl methyl cellulose.
 28. The dosage form of claim 1, whereinthe controlled release topiramate formulation comprises beads comprisingtopiramate dispersed within a delayed release matrix and comprising apolymer selected from methylcellulose, hydroxypropyl methylcellulose,hydroxypropyl cellulose, cellulose acetate, methacrylic acid copolymerand ethylcellulose.
 29. The dosage form of claim 1, wherein thecontrolled release topiramate formulation comprises a topiramate dosageform coated by a gradually hydrolysable material.
 30. The dosage form ofclaim 29 wherein the gradually hydrolysable material comprises one ormore of ethylcellulose, povidone, microcrystalline cellulose andhydroxypropyl methylcellulose.
 31. The dosage form of claim 1, whereinthe controlled release topiramate formulation comprises a corecomprising topiramate, microcrystalline cellulose and methylcelluloseand wherein the core is coated with ethyl cellulose and povidone. 32.The dosage form of claim 8, wherein the unit dosage of phentermine is3.75 mg and the unit dosage of topiramate is 23 mg.
 33. The dosage formof claim 8, wherein the unit dosage of phentermine is 7.5 mg and theunit dosage of topiramate is 46 mg.
 34. The dosage form of claim 8,wherein the controlled release topiramate formulation reaches a maximumplasma concentration at about 8 hours to about 10 hours (Tmax) afteradministration.
 35. The dosage form of claim 8, wherein the controlledrelease topiramate formulation comprises beads comprising a corecomprising topiramate dispersed in a gradually hydrolysable materialcomprising a binder, and a polymeric filler, and wherein the core isprovided with a delayed release coating.
 36. The dosage form of claim 8,wherein the controlled release topiramate formulation comprises a corecomprising topiramate, microcrystalline cellulose and methylcelluloseand wherein the core is coated with ethyl cellulose and povidone.
 37. Apackaged pharmaceutical preparation comprising a plurality of the unitdosage forms of claim 1 in a sealed container and instructions foradministering the dosage forms orally to effect weight loss.
 38. Apackaged pharmaceutical preparation, comprising a plurality of the unitdosage forms of claim 1 each in a discrete sealed housing, andinstructions for administering the dosage forms orally to effect weightloss.